Metabolism and Function of Presenilin 1

Neither the normal functions of presenilins nor the mechanism(s) by which familial Alzheimer’s disease (FAD)-linked mutations cause AD have been defined. Presenilin 1 (PS1) is a polytopic membrane protein that is subject to endoproteolytic processing in vivo; PS1 derivatives accumulate to saturable levels and to ~ 1:1 stoichiometry by mechanism(s) that are not fully defined. We show here that the two fragments coassemble. Moreover, we have detected neither interactions between PS1/PS2 and amyloid precursor protein (APP) nor influences of presenilin expression on APP maturation/secretion. To examine the in vivo function(s) of PS1, we developed mice with functionally inactivated PS1 alleles. These animals die before birth and exhibit several developmental defects, including a poorly differentiated vertebral column, a phenotype traced to abnormal segmentation of somites. Whole mount in situ hybridization analyses reveal that specification of somitic cell lineages is apparently unaffected, despite the clear disruption in somite segmentation. However, notable differences in expression of Notch1 and Dll1 mRNAs were observed in PS −/− embryos; in contrast to wild-type embryos in which abundant expression of Notch1 and Dll1 mRNAs are observed in the presomitic mesoderm, the expression of these genes is nearly abolished in the PSl −/− embryos. Hence, PS1 serves to regulate the spatiotemporal expression of Notch1 and Dll1 in the paraxial mesoderm. Finally, we failed to detect any differences in the levels of Aβ42 and Aβ40 in brains of mice heterozygous for PS1 relative to wild-type litter mates. Thus, mutations in PS1 probably cause AD not by the loss but rather by the gain of deleterious function of mutant polypeptides.